Nicotinamide counteracts Rotenone-induced mitochondrial and neuronal dysfunction in a translational early-life model.

Mitochondrial function is essential for key neurodevelopmental processes, including cellular proliferation, differentiation, migration, synaptogenesis, and synaptic pruning. Previous research from our group demonstrated that neonatal administration of Rotenone (Rot), a mitochondrial complex I inhibitor, led to mitochondrial dysfunction and schizophrenia-like behavioral phenotypes. In this study, we aimed to identify possible cellular pathways disrupted by Rot exposure that may underlie these behavioral alterations. Thus, primary cortical neurons were treated with 1.325 nM Rot for 24 h, a concentration extrapolated from cortical levels observed in the neonatal Rot model. This treatment impaired mitochondrial complex I activity, decreased superoxide production, disrupted mitochondrial respiration and dynamics, reduced dendritic branching, and decreased synapse formation. Notably, pretreatment with Nicotinamide (NAM), a NAD precursor, improved mitochondrial function, reversing these effects. Altogether, our findings underscore the critical role of mitochondrial integrity in neurodevelopment and its potential contribution to neurodevelopmental disorders such as schizophrenia.